This proposal is for a Mentored Clinical Scientist Development Award. The candidate's general career goal as a neuropathologist and research scientist is to advance our understanding of, and relationship between, epilepsy and brain injury. The proposed project focuses on non-neuronal correlates and contributions to epileptogenesis in temporal lobe epilepsy, in both human and animal models. Training aspects of the proposal arise from the strong neuroscience community at the University of Washington, and particularly from the applicant's involvement with adult and child epilepsy surgery centers and associated clinical and basic science research laboratories, Contribution to career development will be made via participation in journal clubs, attending and presenting at clinical and basic science conferences, and research activities in a mentored environment, The applicant's mentor has extensive experience in carrying out epilepsy research and a history of successful mentorships. Expertise of specific consultants includes electroencephalography, regulation of microglia and astrocyte proliferation, and patch clamp electrophysiology. The research project focuses on the role of non-neuronal cellular elements in temporal lobe epilepsy. He will first determine the relationship between astrocyte and microglia reactivity to neuron degeneration in hippocampus, entorhinal and perirhinal cortices in rodent models of seizures, epilepsy and ischemia. Regional quantitation of reactive astrocytes and microglia will be compared with the distribution of neuron loss and degeneration. Tissue from resected human epileptic temporal lobe will be studied by similar techniques. Second, using the rodent kainic acid epilepsy model and varying seizure number with antiepileptic medication, the applicant will quantify reactive astrocytes/microglia to investigate their relationship with seizure activity. Third, to determine if microglia have a possible role in the genesis of epilepsy, the macrophage/microglial response will be manipulated directly with lipopolysaccharide (a systemic macrophage promoter) or macrophage migration inhibition factor (MIF) during kainic acid induction of epilepsy. Finally the electrophysiology of reactive glial elements in animal epilepsy models and human resected tissue will be studied using patch clamp recording techniques.